Cadherins are cell-cell adhesion glycoproteins that form calcium-dependent intercellular junctions and play an essential role in morphogenesis and in the development and maintenance of adult tissues and organs (Conacci-Sorrell M, et al., J Clin Invest, 109:987-91, (2002)). During embryogenesis, the cell expression of specific cadherins results in homophilic interactions that are critical in the process of cell sorting and tissue stratification (Nose A, et al., Cell, 54:993-1001, (1988), Steinberg M S, et al., Proc Natl Acad Sci USA, 91:206-9, (1994) and Takeichi M. Science, 251:1451-5, (1991)). Alterations in these cellular attachments play an important role in cell destabilization and may modify the carefully regulated differentiation process of the epithelial structures (Daniel C W, et al., Dev Biol, 169:511-9, (1995) and Nose A and Takeichi M. J Cell Biol, 103:2649-58, (1986)). For this reason, the functional loss or overexpression of cadherins and the molecular mechanisms underlying the control of the genes codifying these proteins have been implicated in carcinogenesis (Behrens J. Cancer Metastasis Rev, 18:15-30 (1999)).
The cadherin family is subdivided into various subfamilies, including the classical E-, P-, and N-cadherins, each demonstrating a specific tissue distribution (Takeichi M. Development, 102:639-55 (1988)). Although E-cadherin is expressed in all epithelial tissues, the expression of P-cadherin (CDH3) is only restricted to the basal or lower layers of stratified epithelia, including prostate and skin, and also to the breast myoepithelial cells (Takeichi M. J Cell Biol 103:2649-58, (1986) and Shimoyama Y, et al., Cancer Res, 49:2128-33 (1989)).
A large body of evidence now also reveals that aberrant P-cadherin expression is associated with cell proliferation and with tumors of the colon, breast, lung, thyroid, and cervix (Gamallo, Modern Pathology, 14:650-654, (2001); and Stefansson, et al., J. Clin. Oncol. 22(7):1242-1252 (2004)). Human P-cadherin was reported to be the antigen recognized by the NCC-CAD-299 monoclonal antibody raised against a vulvar epidermoid carcinoma (Shimoyama, et al., Cancer Res., 49:2128-2133 (1989)). Modulation of P-cadherin mediated adhesion and intracellular signaling is expected to result in decreased proliferation and survival of tumor cells in vivo. Accordingly, in view of the pivotal role that P-cadherin appears to possess in cell proliferation and solid tumor progression, it is desirable to generate antibodies to P-cadherin that can provide a therapeutic benefit to patients with a variety of cancers.
Monoclonal antibodies against cancer-specific molecules have been proved to be useful in cancer treatment (Harris, M. (2004). Lancet Oncol, 5, 292-302.). In addition to successful examples of clinical application of the humanized or chimeric antibodies such as trastuzumab (Baselga, J. (2001). Oncology, 61, Suppl 2 14-21.), rituximab (Maloney, D. G., et al. (1997). Blood, 90, 2188-2195.) and bevacizumab (Ferrara, N., et al. (2004). Nat Rev Drug Discov, 3, 391-400.) for breast cancer, malignant lymphoma and colon cancer, a number of monoclonal antibodies against other molecular targets are in development and being evaluated their anti-tumor activities. These monoclonal antibodies are expected to provide a hope to patients having tumors that have no effective treatment. One of the other important issues for these monoclonal antibodies is achievement of selective therapeutic effects to cancer cells without severe toxicity due to their specific reaction to cells expressing target molecules (Crist, W. M., et al. (2001). J Clin Oncol, 19, 3091-3102.; Wunder, J. S., et al. (1998). J Bone Joint Surg Am, 80, 1020-1033.; Ferguson, W. S. and Goorin, A. M. (2001). Cancer Invest, 19, 292-315, WO2002/097395, WO2004/110345, WO2006/114704, WO2007/102525.).